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Glycobiology Advance Access published online on February 3, 2006
Glycobiology, doi:10.1093/glycob/cwj085
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received July 1, 2005
Revised January 23, 2006
Accepted January 28, 2006

Article

Hyaluronan oligosaccharides induce cell death through PI3-K/Akt pathway independently of NF-{kappa}B transcription factor

Laura Alaniz 1 *, Mariana G. García 2, Carola Gallo-Rodriguez 3, Rosalía Agusti 4, Norma Sterín-Speziale 5, Silvia E. Hajos 6 {infty}, and Elida Alvarez 6 {infty}

1 Cátedra de Inmunología-IDEHU, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, UBA- CONICET. Buenos Aires, Argentina; Fellow from CONICET
2 Cátedra de Inmunología-IDEHU, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, UBA- CONICET. Buenos Aires, Argentina; Fellow from UBA
3 Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (UBA), CIHIDECAR-CONICET. Buenos Aires, Argentina; Members of the National Research Career (CONICET)
4 Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (UBA), CIHIDECAR-CONICET. Buenos Aires, Argentina
5 Departamento de Ciencias Biológicas, Facultad de Farmacia y Bioquímica, UBA, IQUIFIB-CONICET. Buenos Aires, Argentina; Members of the National Research Career (CONICET)
6 Cátedra de Inmunología-IDEHU, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, UBA- CONICET. Buenos Aires, Argentina; Members of the National Research Career (CONICET)

* To whom correspondence should be addressed.
Laura Alaniz, E-mail: laualaniz{at}ffyb.uba.ar


  Abstract

Several studies indicate that hyaluronan (HA) oligosaccharides are able to modulate growth and cell survival in solid tumors, however, no studies have been undertaken to analyze the effect of HA oligosaccharides (oHA) on T lymphoid disorders. In this work we showed that oHA were able to induce apoptosis in lymphoma cell lines. Since PI3-K/Akt and NF-{kappa}B are major factors involved in cell survival and anti-apoptotic pathways in lymphoma cells, we hypothesized that oHA could induce apoptosis trough inhibition of these pathways. oHA were identified by a method which allows characterization of length using a high pH anion exchange chromatography with pulse amperometric detection (HPAEC-PAD). oHA inhibited PIP3 production (principal product of PI3-K activity) and reduced Akt phosphorylation levels, similarly to the specific inhibitor wortmannin. However, treatment with either oHA or wortmannin failed to inhibit constitutive NF-{kappa}B activity and modulate I{kappa}B{alpha} protein levels, suggesting that PI3-K and NF-{kappa}B signaling pathways are not related in the cell lines used. Cell behavior differed using native HA, which induced PIP3 production, Akt phosphorylation and NF-{kappa}B activation, although not related with cell survival since treatment with native HA showed no effect on apoptosis. Our results suggest that oHA induce apoptosis by suppression of PI3-K/Akt cell survival pathway without involving NF-{kappa}B activation, through a mechanism that differs from the one mediated by native HA.

Keywords: apoptosis/hyaluronan oligomers/HPAEC-PAD/NF-{kappa}B/PI3-K/Akt.

{infty} Both authors contributed equally to this work


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